NAC for Treatment of Oxidative Stress in Chronic Fatigue Syndrome

描述（由申请人提供）：申请人最近的一项体内质子磁共振波谱（1H MRS）研究记录了谷胱甘肽（GSH）（活组织中最丰富和最重要的抗氧化剂）的平均皮质水平降低36%， 慢性疲劳综合征（CFS）与健康对照组相比。这一发现，沿着先前的可靠报告，CFS中氧化损伤的血液标志物增加，强烈暗示了该疾病的病理生理学中氧化应激增加，并表明基于恢复皮质GSH水平以使氧化应激正常化的治疗策略的可行性。然而，由于GSH通过血脑屏障（BBB）或脑屏障的渗透性差，因此直接膳食补充GSH在增加皮质抗氧化剂水平方面并不可行。 大多数细胞的膜，包括神经元。另一方面，由于半胱氨酸的生物利用度-一种具有有利的BBB和膜转运特性的常见氨基酸-在GSH合成途径中是限速的，因此研究这种氨基酸的无毒衍生物N-乙酰半胱氨酸（NAC）作为合成前体具有很大的兴趣，该合成前体可以通过饮食方式提供以刺激脑GSH的原位升高。（a）研究每日补充2000 mg NAC 4周是否会使15名CFS患者与15名匹配的健康对照受试者相比的皮质GSH升高，如通过1H MRS在体内测量的;（B）确定由NAC引起的GSH升高（如果有的话）是否会使CFS中的氧化应激“正常化”，如通过来自所有参与者的体液样品中已确立的氧化应激标志物水平的变化所评估的;以及（c）探索皮质GSH和氧化应激标志物水平的正常化是否与CFS症状的改善相关。如果成功，这项研究有可能（i）提供进一步的证据支持CFS的新兴氧化应激模型，（ii）确定NAC补充是否会导致体内皮质GSH升高，以及（iii）提供干预是否改善CFS症状的初步证据，这将证明NAC或其他GSH前体作为CFS潜在神经保护治疗的更大研究是合理的。 公共卫生相关性：最近的研究发现，慢性疲劳综合征（CFS）患者的主要组织抗氧化剂谷胱甘肽（GSH）水平显著降低，氧化损伤标志物水平升高，这表明该疾病的病理生理学中氧化应激增加，从而为探索性/开发性（R21）研究提供了令人信服的理由，以评估（a）每日补充2000 mg GSH合成前体N-乙酰半胱氨酸（NAC）4周是否会使皮质GSH正常化，如通过质子磁共振波谱（1H MRS）在15名CFS患者中直接体内测量的，与15名匹配的对照受试者和基线相比;（B）GSH的正常化是否也会使CFS中的氧化应激正常化，如通过体液中确定的氧化损伤标志物的水平所评估的;和（c）使皮质GSH和氧化应激正常化是否改善CFS症状。如果成功的话，这项研究可能会提供进一步的证据来支持CFS的新兴氧化应激模型;确定NAC补充是否会提高体内皮质GSH并降低氧化应激;并提供一个令人信服的理由，以进一步研究NAC或其他GSH前体在更大的研究中作为CFS的潜在神经保护治疗-目前这是一个难以捉摸和未满足的需求。

DESCRIPTION (provided by applicant): A recent in vivo proton magnetic resonance spectroscopy (1H MRS) study by the applicants has documented a 36% decrease in mean cortical levels of glutathione (GSH), the most abundant and important antioxidant in living tissue, in chronic fatigue syndrome (CFS) compared to healthy control subjects. This finding, along with prior credible reports of increased blood markers of oxidant damage in CFS, strongly implicates increased oxidative stress in the pathophysiology of the disorder, and suggests the viability of treatment strategies based on restoring cortical GSH levels to normalize oxidative stress. However, direct dietary supplementation of GSH has not proved viable in increasing cortical levels of the antioxidant due to its poor permeability through the blood-brain barrier (BBB) or the membranes of most cells, including neurons. On the other hand, since the bioavailability of cysteine - a common amino acid with favorable BBB and membrane transport properties - is rate-limiting in the GSH synthesis pathway, there is a great deal of interest in investigating the non-toxic derivative of this amino acid, N-acetylcysteine (NAC), as a synthetic precursor that can be supplied through dietary means to spur in situ elevation of brain GSH. These considerations suggested the main objectives of the present Exploratory/Developmental (R21) project, which are: (a) to investigate whether 4 weeks of daily supplementation with 2000mg of NAC will elevate cortical GSH, as measured in vivo by 1H MRS, in 15 patients with CFS compared to 15 matched healthy control subjects and to baseline; (b) to determine whether GSH elevations due to NAC, if any, would "normalize" oxidative stress in CFS, as assessed by changes in the levels of established makers of oxidative stress in body fluid samples from all participants; and (c) to explore whether normalization of levels of cortical GSH and oxidative stress markers will be associated with amelioration of CFS symptoms. If successful, this study has the potential to (i) contribute further evidence in support of the emerging oxidative stress model of CFS, (ii) to establish whether NAC supplementation leads to in vivo elevations of cortical GSH, and (iii) to provide preliminary evidence on whether the intervention ameliorates CFS symptoms, which would justify larger studies of NAC or other GSH precursors as potential neuroprotective treatments for CFS. PUBLIC HEALTH RELEVANCE: Recent findings of robust decreases in the levels of the primary tissue antioxidant, glutathione (GSH), and of increased levels of markers of oxidant damage in patients with chronic fatigue syndrome (CFS), have implicated increased oxidative stress in the pathophysiology of the disorder, thereby providing a compelling justification for thi Exploratory/Developmental (R21) research to assess (a) whether 4 weeks of daily supplementation with 2000mg of the GSH synthetic precursor N-acetylcysteine (NAC) would normalize cortical GSH, as measured directly in vivo by proton magnetic resonance spectroscopy (1H MRS) in 15 patients with CFS compared to 15 matching control subjects and to baseline; (b) whether normalization of GSH would also normalize oxidative stress in CFS, as assessed by levels of established oxidative damage markers in body fluids; and (c) whether normalizing cortical GSH and oxidative stress improves CFS symptoms. If successful, this research could potentially contribute further evidence in support of the emerging oxidative stress model of CFS; establish whether NAC supplementation elevates in vivo cortical GSH and decreases oxidative stress; and provide a compelling rationale to further investigate NAC or other GSH precursors in larger studies as potential neuroprotective treatments for CFS - currently an elusive and unmet need.